This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prevalentce of diagnosed type 2 diabetes mellitus (DM) is currently increasing and is expected to affects 5.4% of adults by the year 2025. Affected individuals have a high risk of blindness, renal failure, amputations, myocardial infarction, stroke and other problems. DM increases the risk of cardiovascular disease (CV) 2-3 fold in men and 3-4 fold in women. Recent observations suggest that even pre-diabetic glucose levels increase CV risk. This highlights the potential health and economic benefits of both preventing DM and reducing CV risk by lowering glucose levels in people wih impaired glucose tolerance (IGT) and other 'pre-diabetic' states. To date there has been no effective and widely applicable method of preventing DM. Progressive high plasma glucose levels in the non-DM range predict an increased DM risk. A recent meta-analysis of 6 longitudinal studies reported that 5% of middle-aged individuals wih IGT develop diabetes annually. For IGT individuals who also had an elevated fasting plasma glucose the rate was approximately 5.8%/year. As IGT is the best studied risk factor for DM that predicts a consistency high incidence across different populations, it will be used as the eligibility criteria for this trial. Ramipril has direct effects o nthe renin-angiotensin-kellikrein system. It may prevent diabetes through effects on the beta cell and by vascular and metabolic effects on muscle (partially mediated by nitric oxide) that may amplify the effects on insulin. Ramipril's effects on insulin sensitivity appear to be indirect. Rosiglitazone's effect appears to be mediated directly through improved insulin improved insulin sensitivity and a possible beta cell cytoprotective effect; it does not appear to directly affect the renin-angiotensin-kallikrein system. The DREAM trial is a large, international, multi-center, randomized, double-blind, placebo controlled trial. A total of at least 4000 participants with IGT will be recruited from major international centers over an 18 month period. They will be randomly allocated to either ramipril and / or rosiglitazone using a 2x2 factoral design and followed for at least 3 years after randomization. Participants will be assessed at regular intervals to ascertain the occurence of the primary outcome (new onset diabetes or all cause mortality) and other secondary outcomes. A diagnosis of diabetes will be made if 2 consecutive plasma glucose levels exceed the diagnostic threholds (i.e. a fasting plasma glucose>=7.0mml/l(126mg/dl) or a 2 hr plasma glucose>=11.1mmol/l (200mg/dl) within a 3 month period.
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